The proper functions of cortical circuits are dependent upon both appropriate neuronal subtype specification and their maturation to receive appropriate signaling. These events establish a balanced circuit that is important for learning, memory, emotion, and complex motor behaviors. Recent research points to mRNA metabolism as a key regulator of this development and maturation process. Hu antigen D (HuD), an RNA-binding protein, has been implicated in the establishment of neuronal identity and neurite outgrowth in vitro. Therefore, we investigated the role of HuD loss of function on neuron specification and dendritogenesis in vivo using a mouse model. We found that loss of HuD early in development results in a defective early dendritic overgrowth phase and pervasive deficits in neuron specification in the lower neocortical layers and defects in dendritogenesis in the CA3 region of the hippocampus. Subsequent behavioral analysis revealed a deficit in performance of a hippocampus-dependent task: the Morris water maze. Further, HuD knock-out (KO) mice exhibited lower levels of anxiety than their wild-type counterparts and were overall less active. Last, we found that HuD KO mice are more susceptible to auditory-induced seizures, often resulting in death. Our findings suggest that HuD is necessary for the establishment of neocortical and hippocampal circuitry and is critical for their function.

Background Serious bacterial infections associated with substance use often result in long hospitalizations, premature discharges, and high costs. Out-of-hospital treatment options in people with substance use disorder (SUD) are often limited. Methods We describe a novel multidisciplinary and interprofessional care conference, “OPTIONS-DC,” to identify treatment options agreeable to both patients and providers using the frameworks of harm reduction and patient-centered care. We retrospectively reviewed charts of patients who had an OPTIONS-DC between February 2018 and July 2019 and used content analysis to understand the conferences’ effects on antibiotic treatment options. Results Fifty patients had an OPTIONS-DC during the study window. Forty-two (84%) had some intravenous (IV) substance use and 44 (88%) had an active substance use disorder. Participants’ primary substances included opioids (65%) or methamphetamines (28%). On average, conferences lasted 28 min. OPTIONS-DC providers recommended out-of-hospital antibiotic treatment options for 34 (68%) of patients. OPTIONS-DC recommended first line therapy of IV antibiotics for 35 (70%) patients, long-acting injectable antibiotics for 14 (28%), and oral therapy for 1 (2%). 35 (70%) patients that had an OPTIONS-DC completed an antibiotic course and 6 (12%) left the hospital prematurely. OPTIONS-DC expanded treatment options by exposing and contextualizing SUD, psychosocial risk and protective factors; incorporating patient preferences; and allowing providers to tailor antibiotic and SUD recommendations. Conclusions OPTIONS-DC is a feasible intervention that allows providers to integrate principles of harm reduction and offer patient-centered choices among patients needing prolonged antibiotic treatment.

Background The SARS-COV-2 pandemic rapidly shifted dynamics around hospitalization for many communities. This study aimed to evaluate how the pandemic altered the experience of healthcare, acute illness, and care transitions among hospitalized patients with substance use disorder (SUD). Methods We performed a qualitative study at an academic medical center in Portland, Oregon, in Spring 2020. We conducted semi-structured interviews, and conducted a thematic analysis, using an inductive approach, at a semantic level. Results We enrolled 27 participants, and identified four main themes: 1) shuttered community resources threatened patients’ basic survival adaptations; 2) changes in outpatient care increased reliance on hospitals as safety nets; 3) hospital policy changes made staying in the hospital harder than usual; and, 4) care transitions out of the hospital were highly uncertain. Discussion Hospitalized adults with SUD were further marginalized during the SARS-COV-2 pandemic. Systems must address the needs of marginalized patients in future disruptive events.

Failures of self-regulation in problem and pathological gambling (PPG) are thought to emerge from failures of top-down control, reflected neurophysiologically in a reduced capacity of prefrontal cortex to influence activity within subcortical structures. In patients with addictions, these impairments have been argued to alter evaluation of reward within dopaminergic neuromodulatory systems. Previously we demonstrated that augmenting dopamine tone in frontal cortex via use of tolcapone, an inhibitor of the dopamine-degrading enzyme catechol-O-methyltransferase (COMT), reduced delay discounting, a measure of impulsivity, in healthy subjects. To evaluate this potentially translational approach to augmenting prefrontal inhibitory control, here we hypothesized that increasing cortical dopamine tone would reduce delay discounting in PPG subjects in proportion to its ability to augment top-down control. To causally test this hypothesis, we administered the COMT inhibitor tolcapone in a randomized, double-blind, placebo-controlled, within-subject study of 17 PPG subjects who performed a delay discounting task while functional MRI images were obtained. In this subject population, we found that greater BOLD activity during the placebo condition within the right inferior frontal cortex (RIFC), a region thought to be important for inhibitory control, correlated with greater declines in impulsivity on tolcapone versus placebo. Intriguingly, connectivity between RIFC and the right striatum, and not the level of activity within RIFC itself, increased on tolcapone versus placebo. Together, these findings support the hypothesis that tolcapone-mediated increases in top-down control may reduce impulsivity in PPG subjects, a finding with potential translational relevance for gambling disorders, and for behavioral addictions in general.

Gambling disorder is a behavioral addiction associated with impairments in value-based decision-making and cognitive control. These functions are thought to be regulated by dopamine within fronto-striatal circuits, but the role of altered dopamine neurotransmission in the etiology of gambling disorder remains controversial. Preliminary evidence suggests that increasing frontal dopamine tone might improve cognitive functioning in gambling disorder. We therefore examined whether increasing frontal dopamine tone via a single dose of the catechol-O-methyltransferase (COMT) inhibitor tolcapone would reduce risky choice in human gamblers (n = 14) in a randomized double-blind placebo-controlled crossover study. Data were analyzed using hierarchical Bayesian parameter estimation and a combined risky choice drift diffusion model (DDM). Model comparison revealed a nonlinear mapping from value differences to trial-wise drift rates, confirming recent findings. An increase in risk-taking under tolcapone versus placebo was about five times more likely, given the data, than a decrease [Bayes factor (BF) = 0.2]. Examination of drug effects on diffusion model parameters revealed that an increase in the value dependency of the drift rate under tolcapone was about thirteen times more likely than a decrease (BF = 0.073). In contrast, a reduction in the maximum drift rate under tolcapone was about seven times more likely than an increase (BF = 7.51). Results add to previous work on COMT inhibitors in behavioral addictions and to mounting evidence for the applicability of diffusion models in value-based decision-making. Future work should focus on individual genetic, clinical and cognitive factors that might account for heterogeneity in the effects of COMT inhibition.

Post-traumatic stress disorder (PTSD) leads to impairments in both cognitive and affective functioning. Animal work suggests that chronic stress reduces dopamine tone, and both animal and human studies argue that changes in dopamine tone influence working memory, a core executive function. These findings give rise to the hypothesis that increasing cortical dopamine tone in individuals with greater PTSD symptomatology should improve working memory performance. In this pharmacological functional magnetic resonance imaging (fMRI) study, 30 US military veterans exhibiting a range of PTSD severity completed an emotional working memory task. Each subject received both placebo and the catechol-O-methyl transferase inhibitor tolcapone, which increases cortical dopamine tone, in randomized, double-blind, counterbalanced fashion. Mnemonic discriminability (calculated with d′, an index of the detectability of working memory signals) and response bias were evaluated in the context of task-related brain activations. Subjects with more severe PTSD showed both greater tolcapone-mediated improvements in d′ and larger tolcapone-mediated reductions in liberally-biased responding for fearful stimuli. FMRI revealed that tolcapone augmented activity within bilateral frontoparietal control regions during the decision phase of the task. Specifically, tolcapone increased cortical responses to fearful relative to neutral stimuli in higher severity PTSD subjects, and reduced cortical responses to fearful stimuli for lower severity PTSD subjects. Moreover, tolcapone modulated prefrontal connectivity with areas overlapping the default mode network. These findings suggest that enhancing cortical dopamine tone may represent an approach to remediating cognitive and affective dysfunction in individuals with more severe PTSD symptoms.

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